Method of Stimulating a Hypoglossal Nerve for Controlling the Position of a Patient&#39;s Tongue

ABSTRACT

A method for controlling a position of a patient&#39;s tongue includes attaching at least one electrode to the patient&#39;s Hypoglossal nerve and applying an electric signal through the electrode to at least one targeted motor efferent located within the Hypoglossal nerve to stimulate at least one muscle of the tongue. Methods may also include the use of more than one contact to target more than one motor efferent and stimulating more than one muscle. The stimulation load to maintain the position of the tongue may be shared by each muscle. The position of the patient&#39;s tongue may be controlled in order to prevent obstructive sleep apnea.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/136,857 filed Oct. 9, 2008 entitled “Method ofSelectively Stimulating a Hypoglossal Nerve”, U.S. Provisional PatentApplication No. 61/161,715 filed Mar. 19, 2009 entitled “Open LoopStimulation of a Hypoglossal Nerve”, and U.S. Provisional PatentApplication No. 61/179,529 filed May 19, 2009 entitled “Open LoopStimulation of a Hypoglossal Nerve”, which are all incorporated byreference herein in their entirety.

BACKGROUND OF THE INVENTION

The present invention generally relates to a method of stimulating aHypoglossal nerve for controlling the position of a patient's tongue. Inone embodiment, the Hypoglossal nerve is stimulated to preventobstructive sleep apnea.

Sleep apnea is a sleep disorder characterized by pauses in breathingduring sleep. Those affected by sleep apnea stop breathing during sleepnumerous times during the night. There are two types of sleep apnea,generally described in medical literature as central and obstructivesleep apnea. Central sleep apnea is a failure of the nervous system toproduce proper signals for excitation of the muscles involved withrespiration. Obstructive sleep apnea (OSA) is caused by episodes ofphysical obstruction of the upper airway channel (UAW) during sleep. Thephysical obstruction is often caused by changes in the position of thetongue 110 during sleep that results in the closure of the soft tissues112 at the rear of the throat or pharynx 132 (See FIGS. 1 and 2A and2B).

OSA is characterized by the complete obstruction of the airway causingbreathing to cease completely (Apnea) or partially (Hypopnea). The humanairway (at the level of the thorax) is lined by soft tissue, anycollapse of its walls results in the closure of the airway which leadsto insufficient oxygen intake, thereby interrupting one's sleep(episodes or micro-arousals).

During sleep, the tongue muscles relax. In this relaxed state, thetongue may lack sufficient muscle tone to prevent the tongue fromchanging its normal tonic shape and position. When the base of thetongue and soft tissue of the upper airway collapse, the upper airwaychannel is blocked, causing an apnea event (See FIG. 2B). Blockage ofthe upper airway prevents air from flowing into the lungs, creating adecrease in blood oxygen level, which in turn increases blood pressureand heart dilation. This causes a reflexive forced opening of the upperairway channel until normal patency is regained, followed by normalrespiration until the next apneaic event. These reflexive forcedopenings briefly arouse the patient from sleep.

OSA is a potentially life-threatening disease that often goesundiagnosed in most patients affected by sleep apnea. The severity ofsleep apnea is determined by dividing the number of episodes of apneasand hypopneas lasting ten seconds or more by the number of hours ofsleep. The resulting number is called the Apnea-Hypopnea Index, or AHI.The higher the index the more serious the condition. An index between 5and 10 is low, between 10 and 15 is mild to moderate, over 15 ismoderately severe, and anything over 30 indicates severe sleep apnea.

Current treatment options range from drug intervention, non-invasiveapproaches, to more invasive surgical procedures. In many of theseinstances, patient acceptance and therapy compliance is well belowdesired levels, rendering the current solutions ineffective as along-term solution.

Current treatment options for OSA have not been consistently effectivefor all patients. A standard method for treating OSA is ContinuousPositive Airway Pressure (CPAP) treatment, which requires the patient towear a mask through which air is blown into the nostrils and mouth tokeep the airway open. Patient compliance is poor due to discomfort andside effects such as sneezing, nasal discharge, dryness, skinirritation, claustrophobia, and panic attacks. A surgical procedurewhere rigid inserts are implanted in the soft palate to providestructural support is a more invasive treatment for mild to moderatecases of OSA. Alternate treatments are even more invasive and drastic,including uvulopalatopharyngoplasty and tracheostomy. However, surgicalor mechanical methods tend to be invasive or uncomfortable, are notalways effective, and many are not tolerated by the patient.

Nerve stimulation to control the position of the tongue is a promisingalternative to these forms of treatment. For example, pharyngealdilation via Hypoglossal nerve (XII) stimulation has been shown to be aneffective treatment method for OSA. The nerves are stimulated using animplanted electrode to move the tongue and open the airway during sleep.In particular, the medial XII nerve branch (i.e., in. Genioglossus), hasdemonstrated significant reductions in UAW airflow resistance (i.e.,increased pharyngeal caliber). While electrical stimulation of nerveshas been experimentally shown to remove or ameliorate certain conditions(e.g., obstructions in the UAW), current implementation methodstypically require accurate detection of a condition (e.g., a muscularobstruction of the airway or chest wall expansion), selectivestimulation of a muscle or nerve, and a coupling of the detection andstimulation. These systems rely on detection of breathing and/ordetection of apnea events as pre-conditions to control and deliverelectrical stimulation in order to cause only useful tongue motions andto periodically rest the tongue muscles and avoid fatigue. In onesystem, for example, a voltage controlled waveform source is multiplexedto two cuff electrode contacts. A bio-signal amplifier connected to thecontacts controls stimulus based on breathing patterns. In anothersystem, a microstimulator uses an implanted single-contact constantcurrent stimulator synchronized to breathing to maintain an open airway.A third system uses an implantable pulse generator (IPG) with a singlecuff electrode attached to the distal portion of the Hypoglossal nerve,with stimulation timed to breathing. This last system uses a leadattached to the chest wall to sense breathing motions by looking at“bio-impedance” of the chest wall. Still another system monitors vagusnerve electroneurograms to detect an apnea event and stimulate theHypoglossal nerve in response.

What is needed is a system and method of electrical stimulation of theHypoglossal nerve for controlling tongue position that is not tied tobreathing and/or detection of an apnea event.

BRIEF SUMMARY OF THE INVENTION

A method of stimulating a Hypoglossal nerve for controlling the positionof a patient's tongue according to some embodiments of the presentinvention includes attaching at least one electrode to the patient'sHypoglossal nerve and applying an electric signal through the electrodeto at least one targeted motor efferent located within the Hypoglossalnerve to stimulate at least one muscle of the tongue. In one embodimentthe at least one electrode is programmable.

In a further embodiment, the method includes programming a thresholdamplitude and pulse duration of the electric signal by attaching the atleast one programmable electrode to the patient's Hypoglossal nervewhile the patient is awake and applying the electric signal to theHypoglossal nerve at a first frequency through the at least oneprogrammable electrode, and increasing at least one of the amplitude andpulse duration of the electric signal until one of the tongue moves andthe patient reports a sensation.

In a further embodiment, the method includes programming a targetamplitude and pulse duration of the electric signal by applying thethreshold amplitude and pulse duration to the patient's Hypoglossalnerve at a second frequency through the at least one programmableelectrode, the second frequency being faster than the first frequency,and increasing at least one of the amplitude and pulse duration of theelectric signal to a target level until the tongue moves sufficiently toopen the patient's airway. In a further embodiment, the method includesdecreasing the second frequency to a target frequency.

In some embodiments, the at least one electrode includes at least firstand second contacts and the electric signal comprises at least first andsecond electric signals, and the method further comprises applying thefirst electric signal through the first contact to a first targetedmotor efferent located within the Hypoglossal nerve to stimulate atleast one muscle of the tongue, and applying the second electric signalthrough the second contact to a second targeted motor efferent locatedwithin the Hypoglossal nerve to stimulate at least one muscle of thetongue. In one embodiment, the at least first and second contactsinclude a plurality of contacts forming a plurality of functionalgroups. In one embodiment, each functional group stimulates a differentmuscle. In one embodiment, each functional group includes at least oneof the plurality of contacts. In one embodiment, the first and secondelectric signals are applied at predetermined intervals. In oneembodiment, the predetermined intervals of the at least one first andsecond electric signals are out of phase with each other. In oneembodiment, the first and second electric signals are generally equal inlevel and frequency. In one embodiment, the first electric signalstimulates a first muscle and the second electric signal stimulates asecond muscle. In one embodiment, the first and second electric signalsare applied at predetermined cycles for alternatively resting andstimulating first and second muscles. In one embodiment, the cessationof the first electric signal is coincident with the initiation of thesecond electric signal.

In one embodiment, the at least one targeted motor efferent is aprotrusor motor efferent. In one embodiment, the at least one targetedmotor efferent is a muscle that moves to improve airway patency. In oneembodiment, the electric signal is applied for a predetermined duration.In one embodiment, the electric signal is automatically applied afterthe patient activates the electrode and following a time delaysufficient to allow the patient to fall asleep. In one embodiment, themuscle is stimulated such that one of apnea and hypopnea is prevented.In one embodiment, the electric signal is applied via an open loopsystem. In one embodiment, the electric signal is applied continuouslyfor an entire sleep period.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofexemplary embodiments of a method of stimulating a Hypoglossal nerve forcontrolling a position of a patient's tongue, will be better understoodwhen read in conjunction with the appended drawings. It should beunderstood, however, that the invention is not limited to the precisearrangements and instrumentalities shown.

In the drawings:

FIG. 1 is an illustration of the human airway;

FIG. 2A is an illustration of an open human airway;

FIG. 2B is an illustration of a closed human airway during an apneaevent;

FIG. 3 is an illustration of the human tongue;

FIG. 4 is a schematic illustration of the motor nerve organization ofthe Hypoglossal nerve;

FIG. 5 is an illustration of the Hypoglossal nerve shown in FIG. 4 withlabeling of the lateral and medial branch nerve fibers;

FIG. 5A is a cross sectional illustration of the Hypoglossal nerve shownin FIG. 5;

FIG. 5B is an illustration of the motor neurons in the Hindbrain;

FIG. 6 is a schematic illustration of the Hypoglossal nerve shown inFIG. 4 with labeling of the lateral and medial branch nerve fibers;

FIG. 7 is a schematic illustration of the Hypoglossal nerve shown inFIG. 4 with labeling of the medial branch nerve fibers;

FIG. 8A is an illustration of a cross-section of a human Hypoglossalnerve;

FIG. 8B is an illustration of a cross-section of a human Lingual nerve;

FIG. 8C is an illustration of a cross-section of a rat Hypoglossalnerve;

FIG. 9 is an exemplary set of fatigue curves of human quadriceps muscleshowing maximum voluntary contraction, 50 Hz electrical stimulation andtwitch responses;

FIG. 10 is an exemplary illustration of an electrode attached to apatient's Hypoglossal nerve;

FIG. 11 is a perspective view of the electrode shown in FIG. 10;

FIG. 12 is a perspective view of the electrode shown in FIG. 11 showingthe plurality of contacts;

FIG. 13 is a graphical representation of an exemplary stimulationstrategy;

FIG. 14A is a graphical representation of an exemplary duty cyclestimulation strategy;

FIG. 14B is a graphical representation of an exemplary interleavedstimulation strategy;

FIG. 14C is a graphical representation of an exemplary synchronousstimulation strategy;

FIG. 14D is a graphical representation of an exemplary asynchronous orrandom stimulation strategy; and

FIG. 15 is an exemplary strength-duration curve.

DETAILED DESCRIPTION OF THE INVENTION Tongue Muscle Properties

Referring to FIGS. 1 and 3, the tongue 110 has been described as ahydrostat—a specialized muscle able to move and change shape without theusual tendon connections to bones against which forces may be applied.Much like the trunk of an elephant, the tongue 110 can change shape andmove within the oral cavity to aid in speaking, eating, and breathing.The tongue muscles include the Genioglossus muscle 114, the Styloglossusmuscle 116, the Hyoglossus muscle 118, the Palatoglossus muscle (notshown), the Geniohyoid muscle 320 (the Geniohyoid muscle 320 is not atongue muscle but it is an important protrusor and pharyngeal dilator)and several muscles that lie within the tongue, called the intrinsics.In a patient who is awake, the brain supplies neural drive to thesemuscles through the Hypoglossal nerve 322, to move the tongue 110 and tochange its shape. The Hypoglossal nerve 322 includes a Styloglossusbranch 316 a, Hyoglossus branches 318 a, Genioglossus branches 314 a,and Geniohyoid branches 320 a. In a patient who is awake, the neuraldrive to the tongue muscles act to maintain tongue shape and position,preventing the tongue 110 from blocking the airway.

The tongue 110 comprises both intrinsic and extrinsic lingual muscles.There are four intrinsic—i.e., origin and insertion within the tongue110—lingual muscles: Verticalis 124, Transversalis 126, SuperiorLongitudinalis 128, and Inferior Longitudinalis 130. There are fourextrinsic—i.e., external bony origin and insertion in to the tonguebase—lingual muscles (mentioned above): Genioglossus 114, Styloglossus116, Hyoglossus 118, and Palatoglossus. The lingual muscles are alsofunctionally categorized as either retrusor or protrusor muscles andboth intrinsic and extrinsic muscles fall into these category. Theretrusor lingual muscles include the intrinsic Superior and InferiorLongitudinalis muscles 128, 130 and the extrinsic Hyoglossus muscle 118and Styloglossus muscle 116. The protrusor lingual muscles include theintrinsic Verticalis and Transversalis muscles 124, 126 and theextrinsic Genioglossus muscle 114. The elevation of the tongue 110 isachieved by the contraction of the Styloglossus muscle 116 while thedepression is the result of downward movements of Hyoglossus andGenioglossus muscles 118, 320.

Hypoglossal Nerve Efferents

FIG. 4 schematically illustrates the motor nerve organization of theHypoglossal nerve 322 from its origin in the motor nuclei 444 in theHindbrain 446—specifically the location of the retrusor and protrusorcell bodies 448, 450—extending via their axons to the retrusor muscle452 and protrusor muscle 454 innervated by the lateral 422 a and medial422 b branches, respectively of the Hypoglossal nerve 322.

Referring to exemplary FIGS. 5-7, the present invention's novel methodof mapping Hypoglossal nerve efferents was demonstrated in a rat usingdyes DiI 556 (for example,1,1′-dioleyl-3,3,3′,3′-tetramethylindocarbocyanine methanesulfonate) andDiO 558 (for example, 3,3′-dilinoleyloxacarbocyanine perchlorate). Inone embodiment, the fluorescent dyes are manufactured by MolecularProbes. The use of the dyes DiI 556 and DiO 558 disclosed a surprisingand unexpected anatomical and topographical organization of theHypoglossal nerve 322. This anatomical and topographical organizationpermits targeted stimulation of portions of the Hypoglossal nerve 322 tomaximize the efficacy of the stimulation as described further below.

In a first experiment, efferents of the medial and lateral branches 422a, 422 b were micro-injected with dyes DiI 556 and DiO 558,respectively. Nerve branches were exposed and the tips of dye-loadedcapillaries were pierced through the perineurium of each branch 422 a,422 b. The dye solution was iontophoresed using a current source (KationScientific, Minneapolis, USA) at 4 μA for five seconds on and fiveseconds off duty cycle for five minutes.

In a second experiment, the Medial branch 422 b and protrusormusculature were surgically exposed and injected with DiI 556. The tipsof dye-loaded capillaries were pierced into the muscle bellies ofselected protrusor muscles 454 and their innervating branches. The dyesolution was iontophoresed using a current source (Kation Scientific,Minneapolis, USA) at 4 μA for five seconds on and five seconds off dutycycle for five minutes.

FIGS. 5 and 6 schematically show the effects of injecting the dyes Da556 and DiO 558 into the lateral and medial branches 422 a, 422 b,respectively, of the Hypoglossal nerve 322. The dye DiI 556 injectedinto the lateral branch 422 a of the Hypoglossal nerve 322 remainsconfined to the Hypoglossal nerve efferents located within the lateralbranch 422 a and spreads rostrally towards the retrusor muscles 452 andanteriorly towards the location of the retrusor cell bodies 448 in themotor nuclei 444 in the hindbrain 446. The dye DiO 558 injected into themedial branch 422 b of the Hypoglossal nerve 322 remains confined to theHypoglossal nerve efferents located within the medial branch 422 b andspreads rostrally towards the protrusor muscles 454 and anteriorlytowards the location of the protrusor cell bodies 450 in the motornuclei 444 in the brain 446. FIG. 5B illustrates the DiO and DiI labeledneurons 556, 568.

Referring to FIG. 5A, the magnified section of the lateral branch 422 aof the Hypoglossal nerve 22 demonstrated that it is almost exclusivelycomprised of the DiI illuminated retrusor motor efferents 560.Similarly, a magnified section of the medial branch 422 b of theHypoglossal nerve 322 (not shown) demonstrated that is almostexclusively comprised of the DiO illuminated protrusor motor efferents562. Consistent near segregation was found of the retrusor motorefferents dorsolaterally and the protrusor motor efferentsventromedially.

This anatomical and topographical compartmentalization was confirmed viaa modified labeling protocol. FIG. 7 illustrates that dye DiI 556 may beinjected into either the terminal end of the medial branch 322 b or intothe protrusor musculature 454 and the dye DiI 556 will travel anteriorlyand ventromedially through the Hypoglossal nerve proper 322. A confocalfluorescent image of the entire Hypoglossal nerve 322 demonstrated theconsistent ventromedial localization of the DiI labeled protrusor motorefferents 560 from the medial branch 422 b through the Hypoglossal nerveproper 322 to the brain 446 and high magnification confocal images ofthe DiI labeled axons.

FIGS. 8A, 8B and 8C demonstrate the organization structure of the HumanHypoglossal nerve (FIG. 8A) and the Human Lingual Nerve (FIG. 8B), aswell as the Rat Hypoglossal Nerve (FIG. 8C). The Hypoglossal nerves inboth Human and Rat are afascicular, lacking the clear organizationalstructure present in most peripheral nerves, and which is present in theHuman Lingual Nerve.

It is believed that the non-fascicular structure of the Hypoglossalnerve in rats approximates the structure of the Hypoglossal in humans.Moreover, the over-all musculature (organization of extrinsic andintrinsic muscles) in the rat tongue and the human tongue, is nearlyidentical. U.S. Provisional Patent Application No. 61/136,857 filed Oct.9, 2008 entitled “Method of Selectively Stimulating a HypoglossalNerve”, which has been incorporated by reference in its entirety,discusses and illustrates the similarities between the rat and humantongues in further detail.

It has therefore been demonstrated that the surprising and unexpectedanatomical and topographical compartmentalization forms the basis of thepresent invention which relates to a method of treating, controlling, orpreventing a neurological disorder using selective targeted electricalnerve stimulation of the Hypoglossal nerve proper 22, and moreparticularly to a method of selective electrical stimulation of motorefferents (e.g., retrusor and protrusor motor efferents) of theHypoglossal nerve 322. The words “selective” and “targeted” are usedinterchangeably herein meaning the use of electrodes and current sourcesto selectively activate targeted nerve fibers within a nerve bundle andhence their associated motor groups to achieve a specific motorfunction. In the case of obstructive sleep apnea, electrical stimulationof efferents of the Hypoglossal nerve 322, and more specifically,targeted stimulation of the protrusor motor efferents located inHypoglossal nerve proper 322 and/or the medial branch 422 b, forexample, can open up the airway and maintain the patency of the upperairway channel.

The above described surprising anatomical and topographical organizationmay help to explain some of the failures and limitations of previousHypoglossal nerve stimulation applications. Specifically, electricalstimulation of the whole Hypoglossal nerve proper 322—i.e., the sectionof the Hypoglossal nerve 322 located proximal to its bifurcation intothe medial and lateral branches 422 a, 422 b—resulted in combined(non-specific) contractions of both intrinsic and extrinsic muscles andboth retrusor and protrusor muscles 452, 454. As both the retrusor andprotrusor muscles 452, 454 comprise intrinsic and extrinsic muscles,electrical stimulation of either the medial or lateral branches 422 a,422 b alone results in recruitment of both intrinsic and extrinsicmuscles. Further, stimulation of the Hypoglossal nerve proper 322 mayexcite sensory afferent and motor efferent fiber types. Grossly, thefused contractions of this non-selective stimulation results not only inundesirable sensory stimulation but also presents as a slightipsilateral deviation and retrusion of the tongue 110.

Known stimulation of the Hypoglossal nerve proper has also resulted incases of profound bradycardia which is believed to be related tosecondary vagus nerve stimulation: the Hypoglossal nerve lies againstthe posterior surface of the vagus and superior cervical sympatheticganglion where it exchanges branches of communication, and is unitedwith the inferior vagal ganglion of the vagus by connective tissue.Common forms of electrical stimulation elicit action potentials in thenerve axon that propagate in two directions: towards the desired muscleor end organ, and in the antidromic direction towards the cell body, thesame direction that sensory fibers would normally transfer theirinformation. It is possible that this antidromic activity could beeliciting the secondary vagus nerve activation. A more distal site ofstimulation—e.g., the medial branch 22 b—may avoid unwanted vagal nervereflex and muscle activation because of its more limited neuralconnections, but will still non-selectively recruit both sensoryafferent and motor efferent fiber types if they both exist within therange of the stimulating electrode. By discerning the extent andmyotopic organization of the Hypoglossal nerve motor neuron subgroupsand the muscles(s) thereby innervated, such knowledge can be used tospecify the functional relevance of diverging efferent systems and inelucidating mechanisms underlying tongue control. Accordingly, in oneembodiment, the present invention is directed to a method of mappingHypoglossal nerve fibers, thereby allowing the claimed method ofselective recruitment of specific nerve fibers, as well as methods forselective stimulation. Understanding the neural organization allows forselective targeted stimulation that activates only those muscle groupsthat are desirable, and avoids activating those which are not. Theknowledge gained from animal and cadaver studies validate the methods ofselective stimulation described herein. The process of using selectivestimulation allows for the selective activation of only the desiredmuscle functions.

It should be noted, additionally, that activation of a small fraction ofretrusor muscle or muscles along with the activation of protrusormuscles can act to reduce pharyngeal compliance while not significantlyleading to tongue retrusion, and may have a beneficial effect in airwaypatency.

Apparatus for Stimulation of Hypoglossal Nerve Efferents

Referring to FIGS. 10-12, in one embodiment, an electrode 1064 isattached to the Hypoglossal nerve to apply at least one electric signalto a first targeted motor efferent located within the Hypoglossal nerve322. The electrode 1064 may be programmable. The electrode 1064 mayinclude a plurality of contacts (e.g. contacts 1164 a, 1264 b, 1264 c,1264 d) each applying an electric signal to a targeted motor efferent.In one embodiment, each contact applies an electric signal to adifferent targeted motor efferent. In one embodiment, more than onecontact applies an electric signal to a single targeted motor efferent.In one embodiment, the electrode 1064 includes a first contact (e.g.contact 1164 a) to apply a first electric signal to a first targetedmotor efferent, a second contact (e.g. contact 1264 b) to apply a secondelectric signal to a second targeted motor efferent, a third contact(e.g. contact 1264 c) to apply a third electric signal to a thirdtargeted motor efferent and a fourth contact (e.g. contact 1264 d) toapply a fourth electric signal to a fourth targeted motor efferent. Inone embodiment, the targeted motor efferents that are stimulatedstimulate at least one muscle of the tongue 110 to control the positionof the tongue 110. In one embodiment, the electrode 1064 is abiocompatible, soft material cuff electrode that provides an intimateconnection to the nerve. In another embodiment, a lead wire connects theprogrammable electrode to the control system. In one embodiment, theapparatus does not require a lead wire connecting the programmableelectrode to the control system. In one embodiment, the control systemincludes a battery, either primary or rechargeable, for powering theapparatus. In one embodiment, the control system includes a processorfor setting up stimulation parameters to achieve the desired outcome forthe individual patient or otherwise controlling the stimulation. In oneembodiment, stimulation parameters are selected from the groupconsisting of, but not limited to, stimulation amplitude, stimulationfrequency and stimulation duration. In one embodiment, the controlsystem includes a mechanism that allows the patient to turn theapparatus on and off and possibly make adjustments within preprogrammedsettings.

The method provided by the present invention is not limited by thedesign of the apparatus used to carry it out except to the extent thepoint of contact with the Hypoglossal nerve proper 322 or its lateraland medial branches 422 a, 422 b is consistent with the teachingsherein. Although an exemplary apparatus for selectively stimulatingHypoglossal nerve efferents is shown, equivalent alterations andmodifications will occur to others skilled in the art upon reading andunderstanding this specification and annexed drawings. For example, U.S.Patent Publication No. 2008/0046055, WO 2009/048580 and WO 2009/048581,the contents of which are incorporated herein by reference in theirentirety, can be modified in accordance with the teachings herein forstimulating the Hypoglossal nerve 322. In particular regard to thevarious functions performed by the herein described exemplary apparatus,the terms used to describe the exemplary apparatus are intended tocorrespond to any apparatus that is functionally equivalent—i.e., eventhough not structurally equivalent, that performs the function in theherein illustrated exemplary apparatus of the present invention. Forfurther information regarding an apparatus which may be modified inaccordance to the teachings herein for practicing the method of thepresent invention, refer to U.S. Pat. Nos. 6,456,866 and 6,587,725,which are hereby incorporated herein by reference in their entirety.

Fatigue

FIG. 9 illustrates an exemplary fatigue curve. Fatigue is a commonphenomenon with artificial activation by electrical stimulation of amuscle. In voluntary muscle control, the human brain recognizes,organizes, and selects the best muscle fibers to activate for aparticular activity. It brings fibers in and out of activation tominimize or prevent fatigue and maintain muscle output. In artificialactivation by electrical stimulation however, stimulation comes from oneor more electrode contacts located in a relatively fixed position withrespect to a targeted nerve or nerve fiber bundle. The same populationof fibers are activated essentially every time that a stimulus isapplied because of this fixed relationship.

As is known in the art, excitation of a nerve fiber can occur along astrength duration iso-threshold curve—a nerve fiber will be excited aslong as the amplitude is above the curve or the phase duration is to theright of the curve. An exemplary strength curve is shown in FIG. 15. Ateither end of the curve the shape of the curve is asymptotic—at alimiting phase duration no amount of stimulation current elicits aresponse, and at the other no phase duration is long enough to elicit aresponse either. The invention described here refers to the use ofstimulus amplitude for means of modulating the recruitment of nervefibers, but it shall be understood that many methods, including phaseduration and stimulus amplitude, can be utilized to the same ends ofactivating nerve fibers with electrical stimulation.

Nerve fibers are preferentially activated, or recruited, in the order oftheir proximity to the electrode contact and by their fiber diameter. Asa general rule, the closer a fiber is to the cathodic contact, the morelikely it will be activated (the general form of a stimulating system isto place the cathodal contact in close proximity to the target nerveaxons; other forms of stimulation exist and shall be obvious to thoseskilled in the art). The larger the diameter of a fiber, the more likelyit will be activated. The distance and size distribution in a nervebundle does not change appreciably over time. Hence, the recruitmentproperties—which fibers will be activated with a particular amplitudepulse—do not change either. If the applied stimulus is maintained at asufficiently high enough frequency, the recruited muscle fibersactivated by the stimulated nerve fibers eventually fatigue. Muscleforce and/or position then change to the relaxed, inactivated condition.The stimulation of skeletal muscle for postural control or limb motionis often performed at frequencies that would normally be expected tocause fatigue in those muscles along with the loss of desired functionif the stimulation were maintained continuously. Stimulation may bemodulated by changing the stimulus amplitude, as described above, or bychanging the phase duration of the pulse. Great care and tremendouseffort are expended in avoidance of fatigue in skeletal muscleapplications for fear of loss of desired functional effect, for example,for patients suffering from spinal cord injury or other neurologicaldysfunction.

Fatigue may be minimized or prevented by using a stimulation dutycycle—that is, stimulating for a certain amount of time beforesignificant fatigue sets in, then stopping to let the muscle rest andregain its ability to contract. For obstructive sleep apnea this is lessthan optimal because without an applied stimulus during the off periodof the electrical stimulation duty cycle the tongue would not be drivento maintain a desired position, and could fall back against the rear ofthe throat and allow an apnea event to occur. This is one of the reasonsthat many OSA stimulation systems rely on sensors to detect when toapply stimulation and when to leave it off. The method of using dutycycle to rhythmically apply stimulation has been proposed, also, to doaway with the need to sense breathing events, in the hopes that byintroducing rhythmic stimulation to the Hypoglossal nerve that somehowthe breathing events would synchronize automatically to the stimulationtiming. This has not been proven and the study by Davis, et al, usingmicrostimulators in sheep demonstrated that manual timing of stimulationto the events of breathing was required to achieve a useful outcome insingle point stimulation of the Hypoglossal nerve.

Another method of minimizing or preventing fatigue is to use one or moreindependent current sources to activate multiple portions of the desiredmuscle groups. In certain exemplary embodiments, one or more independentcurrent sources drive one or more contacts (1164 a, 1264 b, 1264 c and1264 d for example shown in FIGS. 11 and 12) that interface with theHypoglossal nerve 322. These contacts are optionally contained in asingle cuff electrode 1064 as shown. Each contact can be activatedseparately or in combination with other contacts.

In certain embodiments, each contact is assigned to one or morefunctional groups. Functional groups may in turn be used to selectregions of fibers within the nerve bundle that result in a desiredtongue movement. The effort of moving the tongue to the desired positionis thus shifted from one functional group to another functional group sothat no single functional group is required to work all of the time.Thus, the effort of moving the tongue is shared among multiplestimulated nerve fibers and their associated muscles, preventing orreducing fatigue because none of the groups is activated long enough tocause significant fatigue, and during their off state they are allowedto recover from the stimulation. In certain exemplary embodiments, eachgroup is active until just before significant fatigue sets in. One ormore other groups are then activated to take its place, allowing theformer muscle group fibers to rest. In one embodiment, the stimulationis spread over more than one contact wherein the duty cycle of eachcontact is overlapped (FIG. 13). In one embodiment, the stimulationpulses may be generally random or pseudo random so long as the overallcontractions per unit of time is limited (see FIG. 14D).

Another method of reducing or eliminating fatigue is to lower thestimulation frequency. The faster a nerve is stimulated, the faster itfatigues. Each pulse produces a contraction, with each contractionrequiring a certain amount of work. The more contractions there are, themore the muscle works, and the more likely the muscle will becomefatigued. Reducing the stimulation frequency to a rate just fast enoughto achieve the desired response minimizes the rate at which musclecontractions occur. This minimizes the amount of work done by themuscle, delaying or minimizing muscle fatigue. In one embodiment, thestimulation is spread over more than one contact wherein each contactdelivers a generally equal fraction of stimulation frequency that is outof phase with the other contacts (FIG. 14B). This method reduces thestimulation rate for each of the independent groups but results in afunctional stimulation rate that is essentially the sum of the ratesthat are active. As shown in FIGS. 14A and 14B, the same effective forceor position is maintained, but in FIG. 12A fatigue is prevented by dutycycle method and in FIG. 14B it is prevented by three groups running atone third the frequency of any one group in FIG. 14A, resulting in thesame muscle force or position and the same prevention of fatigue.Stimulation frequencies that have been used for activating skeletalmuscle have often required the use of a frequency that results intetanus, a smooth fusion of pulses fast enough to maintain a nearcontinuous level of force or position. Tetanus is not required, per se,in the artificial activation of the tongue—the patient is asleep, andthe cosmetic appearance of the tongue while it is activated is notnearly as important as the maintenance of airway patency. Experimentalevidence has shown that stimulating at frequencies below 5 pulses persecond have been adequate to maintain airway patency in patients withsevere OSA.

Continuous or near continuous stimulation of a muscle is discouraged inthe art because of fatigue problems. However, in view of the teachingherein, the tongue 110 is a fatigue resistant muscle. Testing in bothrats and humans has confirmed this finding. In limited animal studies,it was demonstrated that rat tongue muscle could be stimulated at veryhigh frequencies for extended periods without observable changes intongue position. In one study, rather than stimulating at 15 pulses persecond (pps), a frequency adequate to move the tongue sufficiently toclear the rear of the throat, stimulation was applied at supra-thresholdlevels at a frequency of 100 pps. The resulting tongue response wasmaintained for more than one hour before any significant change intongue position could be detected. If the stimulation frequency weredropped to 15 pps, it is likely that stimulation may be applied morethan five times longer before tongue position change would be expectedto occur. In human trials, embodiments disclosed herein successfullystimulated patients with a fixed set of electrode contacts for manyhours before the anti-apnea effect was seen to diminish. In oneembodiment, using lower frequencies and multiple contacts on a humantongue increases the duration that stimulation could be applied beforeanti-apnea effects diminish.

Preventing OSA by Open Loop Stimulation

Certain exemplary methods address this problem by applying constant, ornear-constant electrical stimulation to the Hypoglossal nerve. Thestimulation maintains a sufficient muscle tone by applying an artificialneural drive to the Hypoglossal nerve fibers that preferentially movethe tongue to a position that clears the airway. In certain exemplaryembodiments, open loop stimulation is used. The open loop stimulation inthese embodiments achieves a physical response previously obtained usingsurgical procedures to make a long-term static change in the airwaygeometry during its employment.

The presence or absence of tone is also associated with the mechanism ofthe stiffening of the airway walls, thereby making them less compliantor less easily collapsible. Half of the retroglossal airway is lined bythe back of the tongue while the other half is made up of mid-pharyngealwall. There is a close anatomical and functional relationship betweenthe Tranversalis muscles (intrinsic lingual) and Superior Pharyngealconstrictor muscles 134 at the base of the posterior tongue (Seiji Niimiet. al., Clinical Anatomy, Volume 17 (2), page 93). These two musclescomplement each other in maintaining the airway shape. Movement of thelingual muscles (protrusion or retrusion) not only results in thestiffening of the wall of the posterior tongue but also stretches andstiffens (imparts an indirect drag via Superior Pharyngeal constrictormuscles) the other parts of the pharyngeal wall, making it lesscompliant and thus causing beneficial airway changes that effect airflow.

Thus, with the tongue and associated rear throat tissues consistentlydriven in such a manner as to clear the airway there is no need todetect apneas because they simply will not be allowed to occur. Ratherthan timing stimulation to breathing, or monitoring for an apnea eventprior to initiating treatment, the exemplary embodiments stimulate theHypoglossal nerve in a predetermined manner via an open loop system toactivate targeted muscles in the tongue to maintain airway patency. Withairway resistance decreased and/or the tongue prevented from fallingback against the rear of the throat, anchor pharyngeal compliancereduced, there is no need to monitor for apneas, because they areprevented from occurring, nor monitor for ventilation timing because thestimulation is not timed or synchronized to breathing at all, it ismaintained continuously during the entire sleeping period.

The activation of a protrusor that moves the tongue forward and awayfrom the oral-pharyngeal junction, or the activation of a retrusor thatacts to decrease the compliance of the pharyngeal wall are bothdesirable in preventing the occlusion of the airway. The activation ofintrinsic muscles that change the shape of the tongue may also lead todesirable motions even though the actions of these muscles may not beclearly defined in terms of protrusor or retrusor. It shall beunderstood that the activation of any tongue muscle that achievesbeneficial motions or actions of the tongue musculature is a potentialtarget of the selective targeted methods of electrical stimulation asdescribed by the methods of this patent and it shall not be the singleobject of the described method to only activate protrusors per se.

Since the tongue is a fatigue-resistant muscle, it can be stimulated,using the techniques described herein, for long durations without lossof force or movement. By stimulating the Hypoglossal nerve, tongueactivation resembling normal daytime tongue muscle tone is restored tokey muscles during sleep. The tongue does not fall into the throat,keeping the airway open and allowing the patient to breathe normallyduring sleep. Continuous or near-continuous stimulation maintains thetongue in a desired position, shaping the airway, without the necessityof a complicated closed loop stimulation strategy with the associateddependence upon sensors and their interpretation. While the tonguemusculature is fatigue resistant, it is still susceptible to fatigue ingeneral. Therefore methods employed herein are still directed atmaintaining therapeutic effect by utilization of multiple groups tomaintain desired function and other methods such as frequency control tominimize the work load of any single muscle group.

Problems with Detecting Changes in Respiration

It is difficult to detect an event or a change in respiration and useinformation such as polysomnography data prior, during and after anapnea event, to control delivery of stimulation in an implanted system.With open loop stimulation, stimulation is not timed to breathingactivity, nor is stimulation tied to detecting apnea activity. Detectionof changes in respiration requires the use of sensors, electroniccircuitry to condition the signals received from the sensors, andprocessing algorithms to analyze the data and make decisions about thedata recorded. Sensing often cannot occur directly but by inference fromother signals. Impedance plethysmography depends upon the fact that whenthe chest wall expands with an inspiration that the impedance across thechest changes accordingly. Pressure sensors monitoring thoracicpressures likewise infer breathing activity by correlating pressure tochanges in the breathing cycle. Monitoring the electroneurogram of thevagal or Hypoglossal nerve to either detect breathing events or apneaicevents is likewise extremely difficult. All of these sensors are subjectto noise or disturbance from other sources making the clear distinctionof events more difficult to detect or worse, causing the false detectionof an event. The addition of sensors to an implanted system increasesthe complexity of the leads and header assembly of an implanted pulsegenerator and controller and increases the likelihood for theopportunity for system failure and makes the surgical implantation moredifficult. The added electronic circuitry to condition the sensorsignals adds complexity, cost, and power consumption to the implantedsystem. The requirement to process the conditioned data by amicrocontroller within the implanted system adds further energy cost,software complexity, and the opportunity for misinterpretation of theacquired signals. The additional cost of sensing increases the volume ofthe implanted system and increases its power budget, requiring largerbatteries and longer recharge times. All of these issues are favorablyresolved using a system comparable to the one described by the inventionherein—no sensors are required, no sensor conditioning electronics arerequired, no analysis algorithms are required, and no additional energyor volume are dedicated to sensing and analysis functions.

Problems with Stimulating Whole Hypoglossal Nerve and its DistalBranches

It was previously assumed by early investigators that stimulation of theentire Hypoglossal nerve would result in useful tongue motion despitethe likelihood that the Hypoglossal nerve contains nerve fibers thatinnervate both the tongue's agonistic and antagonistic muscles. Thestimulation of the entire Hypoglossal nerve resulted in only modestchanges in the airway, but which were sufficient when they occurred atthe right time in the breathing cycle. This observation drove the designof electrical stimulation systems for OSA that required detection of thebreathing cycle to time the delivery of stimulation. Others have chosento stimulate more distal branches of the Hypoglossal nerve in the hopesthat if stimulation were applied to these more differentiated branchesthen only the desired tongue muscles would be activated. One problemwith this latter approach is that the surgical approach to these distalbranches is more difficult and the branches are progressively smallerthe more distal the placement of the electrode, making the design of anappropriate electrode for such small branches more difficult and thesystems used to stimulate them less robust and the opportunity fordamage for these more delicate structures more likely.

Stimulating Non-Fasciculated Nerve Bundles

Neurostimulation is often performed on peripheral motor nerves.Peripheral motor nerves emanate from the ventral horns of the spinalcord and travel in bundles to various muscle groups. A single motornerve bundle may contain many sub-groups of neurons. Some neuronsub-groups are organized into separate sub-bundles called fascicles,which are easily viewed in histological cross section, and often connectto groups of muscle fibers within the same muscle. With thesesub-groups, stimulation of the sub-group typically results in activationof a group of muscles working together to achieve a desired effect.

Other peripheral nerves, such as the Hypoglossal nerve, have sub-bundlesthat are not organized into fascicles. Instead, these sub-bundles run insomewhat controlled but less well defined regions of the nerve, and arenot easily recognizable in a cross-sectional view. These sub-groupsoften go to multiple muscle groups in different locations. An example ofsuch a nerve is the Hypoglossal nerve, which has multiple sub-groupsconnecting to different portions of the tongue. A more detaileddescription of the nerve structure for the human tongue is disclosed inU.S. Patent Application No. 61/136,102, filed Oct. 9, 2008, herebyincorporated by reference in its entirety.

Not every muscle of the human tongue is involved in the opening of theairway. Some stimulated muscles act to block the airway. In theembodiments described, the only nerves targeted by the targetedselective electrical stimulation method described herein are nerves thatstimulate muscles that activate the tongue resulting in the optimalopening of the airway and suppression of unwanted tongue movements. Incontrast, whole nerve stimulation activates the entire nerve contentsand nerve bundles containing nerve fibers to both desirable andnon-desirable groups of contracting muscles are simultaneouslyactivated. This not only leads to suboptimal levels of opening, but mayalso produce undesirable tongue motions. A surgical way to avoid thisproblem with less than optimal stimulation methods is to placestimulating electrodes on distal branches of the nerve that onlyinnervate the desired muscle groups, a task that is difficult andpotentially hazardous to the nerve.

In these cases, activation of the entire bundle from an artificialelectrical stimulus results in activation of all of the musclesactivated by the sub-groups within the stimulated nerve group. In thepresent invention, to target only the desired specific groups of fiberswithin a nerve bundle, exemplary embodiments use multiple nerveelectrode contacts and multiple independent controlled current sourcesto activate only the desired sub-groups. This eliminates the problem ofdelivering stimulation to muscles not providing the desired tongueposition.

The nerve in this region is non-fascicular, (proximal to theStyloglossus/Hyoglossus branches and distal to the ansa cervicalisbranch) that is, the various nerve groups that separate distally are notisolated in the bundle as fascicles, but are present en masse with allof the fibers of the Hypoglossal nerve. As described in the rat dyestudies above, and in studies on human cadavers, there appears, however,to be an organization to the bundle, with fibers mostly innervating theGenioglossus muscle residing in the medial region of the bundle. Studiesconducted in rats, an animal model identified thus far that replicatesthe non-fascicular nature of the human Hypoglossal nerve, revealed anorganization of the whole nerve, suggesting that targeted activation ofa sub-population of neurons in the Hypoglossal nerve would be possible.Stimulation studies in rats and humans with multipolar electrodes andmultiple independent current sources verified this with the result thatmultiple distinct motions and positions of the tongue could be achievedusing targeted stimulation methods and devices. Placement of electrodecontacts about the perimeter of the Hypoglossal nerve at this region hasachieved targeted selective activation of the tongue muscles. Theresulting airway changes elicited by stimulation depend upon whichelectrode contacts are activated.

In one exemplary system, an electrode 1064 is implanted around theHypoglossal nerve at or near an approximately 1 cm length of 3.5 to 4.5mm diameter nerve bundles. This is typically at the rear of and belowthe mandible, just underneath the sub-mandibular gland, proximal to theStyloglossus/Hyoglossus branches and distal to the ansa cervicalisbranch. At this point, the major branches to the various tongue musclesare distal to the electrode site.

Targeted Selective Stimulation of Hypoglossal Nerve Efferents

In one embodiment, the present invention is directed to the targetedselective stimulation of Hypoglossal nerve efferents in animals. In oneembodiment, the present invention is directed to the targeted selectivestimulation of Hypoglossal nerve efferents in mammals. In oneembodiment, the present invention is directed to the targeted selectivestimulation of Hypoglossal nerve efferents in rats. In one embodiment,the present invention is directed to the targeted selective stimulationof Hypoglossal nerve efferents in humans.

In one embodiment, the present invention is directed to the targetedselective stimulation of Hypoglossal nerve efferents via electricsignals emitted from at least one programmable electrode contact. In oneembodiment, the targeted selective stimulation of Hypoglossal nerveefferents occurs via multiple electrode contacts. In one embodiment, thetargeted selective stimulation of Hypoglossal nerve efferents is drivenby multiple current sources. In one embodiment, the multiple electrodecontacts are each driven by their own independent current source.

In one embodiment, the multiple electrode contacts each activate abeneficial muscle group and alternate in their operation such that thebeneficial function is maintained by at least one group at all times. Inone embodiment, the multiple electrode contacts each activate abeneficial muscle group and interleave their operation such that thepatency of the airway is maintained. In one embodiment, the multipleelectrode contacts each activate a beneficial muscle, and alternate intheir operation such that the patency of the airway is maintained. Inone embodiment, the multiple electrode contacts each activate one of abeneficial muscle, and interleave their operation such that the patencyof the airway is maintained.

In one embodiment, the method includes activating the ipsilateralGeniohyoid muscle. In one embodiment, the method includes activatingrostral or caudal or both compartments of the ipsilateral Geniohyoidmuscle. In one embodiment, the method includes activating at least onecompartment or both compartments of ipsilateral or with the rostralcompartment of the contralateral Geniohyoid muscles increasing thedilation (of the pharyngeal airway) and the patency of the airwaychannel.

In one embodiment, the modulating electric signals have a frequencysufficient for a smooth tetanic contraction. In one embodiment, themodulating electric signals have a stimulation frequency of about 10 toabout 40 pps. In one embodiment, the modulating electric signals are ofan intensity from about 10 to about 3000 microamps (μA). In oneembodiment, the modulating electric signals have a stimulation pulsewidth of about 10 to about 1000 microseconds (μs).

In one embodiment, the targeted selective stimulation of Hypoglossalnerve efferents activates at least one lingual muscle. In oneembodiment, the targeted selective stimulation of Hypoglossal nerveefferents activates at least one upper airway channel dilator muscle. Inone embodiment, at least one protrusor muscle is activated. In oneembodiment, at least one protrusor muscle and at least one retrusormuscle are alternately activated. In one embodiment, at least oneprotrusor muscle and at least one retrusor muscle are co-activated. Inone embodiment, the at least one protrusor muscle 400 activated is thegenioglossus muscle. In one embodiment, at least one beneficial musclegroup is activated. In one embodiment, at least two beneficial musclegroups are activated.

Method of Treating a Neurological Disorder Including Obstructive SleepApnea

In one embodiment, the present invention is directed to a method oftreating, controlling, or preventing a neurological disorder byattaching at least one programmable electrode to a patient's Hypoglossalnerve proper 322; and selectively applying electric signals to motorefferents located within the Hypoglossal nerve proper 322 through theprogrammable electrode 1064 to selectively stimulate at least onemuscle. In one embodiment, the electric signals are modulating. In oneembodiment, the method of treating, controlling, or preventing aneurological disorder consists essentially of the recruitment ofretrusor motor efferents. In one embodiment, the method comprises therecruitment of protrusor motor efferents. In one embodiment, the methodcomprises the recruitment of a ratio of retrusor to protrusor motorefferents such as the ratios described above to treat a neurologicaldisorder.

In one embodiment, the neurological disorder suitable for treatment,control, or prevention by the present invention is selected from thegroup consisting of, but not limited to oral myofunctional disorders,atrophies, weakness, tremors, fasciculations, and myositis.

In one embodiment, the neurological disorder is obstructive sleep apnea.Other potential applications of this method, in addition to treatment ofobstructive sleep apnea, include, for example, supplemental nervestimulation to keep the airway open for treatment of snoring, hypopnea,or countering motor activation of the tongue during a seizure. Otherhealth problems related to the patency of a patient's airway may also betreated using methods provided by the present invention.

In one embodiment, the present invention provides a method of treating,controlling, or preventing obstructive sleep apnea including the stepsof attaching at least one programmable electrode to a patient'sHypoglossal nerve proper 322; and selectively applying electric signalsto motor efferents located within the patient's Hypoglossal nerve proper322 through the programmable electrode 1064 to selectively stimulate atleast one muscle. In one embodiment, at least one programmable electrode1064 provides a continuous, low level electrical stimulation to specificmotor efferents to maintain the stiffness of the upper airway channelthroughout the respiratory cycle. In one embodiment, at least oneprogrammable electrode provides intermittent electrical stimulation tospecific motor efferents at controlled, predetermined intervalssufficiently close to achieve a constantly opened airway.

In one embodiment, the method of treating, controlling, or preventingobstructive sleep apnea includes selectively activating one or moremuscles in the upper airway channel to effectively reduce the severityof obstructive sleep apnea and improve airway patency. In oneembodiment, the method includes targeted selective stimulation of motorefferents that activate the geniohyoid muscle, causing anterosuperiormovement of the hyoid bone to increase the patency of the upper airwaychannel. In one embodiment, the method includes targeted selectivestimulation of functionally opposite muscles that also effectivelystiffen the upper airway channel to reduce the risk of collapse.

In one embodiment, the method of treating, controlling, or preventingobstructive sleep apnea consists essentially of the recruitment ofprotrusor motor efferents. In one embodiment, the method includesactivating at least one protrusor muscle. In one embodiment, the methodincludes targeted selective stimulation of protrusor motor efferentslocated within the Hypoglossal nerve proper 22 that activate thegenioglossus muscle, causing protrusion of the tongue to increase thepatency of the upper airway channel.

System Programming

System programming and stimulation of the exemplary embodiments do nothave to take into account the timing of respiration. When electricalstimulation is applied to a nerve bundle there are essentially twofactors that determine which fibers within the bundle will be excited.The first is distance of the fiber to the contact—the closer a fiber isto the contact, the higher the current gradient and the more likely thatthe fiber will be excited. The second is the diameter of the fiber,which determines the voltage changes across the membrane and hence thelikelihood of reaching the threshold of generating an actionpotential—the larger the diameter, the more likely that the fiber willbe excited. At a particular current amplitude of sufficient duration,all of the fibers within a certain distance or diameter of thestimulation will be excited. As current amplitude increases, more fiberswill be excited. Since each fiber is associated with a muscle fiber orfibers (jointly referred to as a motor unit), as more nerve fibers areexcited, more muscle fibers are caused to contract, causing a gradationin force production or position as the stimulation current or phaseduration is increased. The point at which this force is first generatedis referred to as the motor threshold, and the point at which all of thefibers are all recruited is the maximum stimulation level. The comfortof this activity to the patient is often exceeded before this maximumlevel is attained, and it is important to determine the threshold leveland the level at which the useful level of force or position is obtainedat a level that is not uncomfortable for the patient. The point at whichthe optimal or best possible force or position is obtained is the targetlevel.

In certain exemplary embodiments, system programming entails operativelyconnecting at least one electrode with a motor efferent located within anerve (for example, the Hypoglossal nerve). This connection need not bea physical connection. The connection can be any connection known tothose skilled in the art where the connection is sufficient to deliver astimulus to the targeted motor efferent of the targeted nerve. Once theelectrode is operatively connected with the targeted nerve, two or moreelectrode contacts are activated to determine their applicable stimulusthresholds (i.e., the threshold at which a desired response isachieved). The level of stimulation comfortable to the patient can alsobe measured. The contacts may also be assigned into functional groupsthat provide tongue motions that are beneficial in maintaining airwaypatency.

In certain exemplary embodiments, stimulation may be provided to thenerve using at least two functional groups. A functional group isdefined as one or more electrode contacts (for example contacts 1164 a,1264 b, 1264 c and 1264 d shown in FIG. 10) that deliver a stimulus thatresults in a tongue movement that maintains an open airway. Eachfunctional group may have a single contact, or may have multiplecontacts. For example, a functional group with two contacts could beused to excite a population of nerve fibers that lie between twoadjacent contacts. A non-limiting example of how stimulation from thefunctional group can be delivered is field or current steering,described in International Patent PCT/US2008/011599, incorporated byreference in its entirety. In another exemplary embodiment, two or moreadjacent contacts may be used to focus the stimulation field to limitthe area of excited neurons to a smaller area than what might beachieved with a single contact using a pulse generator case as a returncontact. In another exemplary embodiment, two or more non-adjacentcontacts may be used together to generate a useful response that isbetter than the response by the single contacts alone could produce. Thetable below shows various exemplary combinations of functional groupsfor an embodiment having six contacts numbered 1-6. A single contact canbe a member of more than one functional group. For example, contact twocould be in two different groups—one group made up of contact 1 and 2,and another group made up of contact 2 and 3. Exemplary contact groupsare shown below.

a. Single Contact Groups: 1, 2, 3, 4, 5, 6

b. Double Contact Groups: 1&2, 2&3, 3&4, 4&5, 5&6, 6&1

c. Triple Contact Groups: 1&2&3, 2&3&4, 3&4&5, 4&5&6, 5&6&1, 6&1&2

d. Non-Adjacent Contact Groups: 1&3, 2&4, 3&5, 4&6, 5&1, 1&3&5, 2&4&6,3&5&1,

FIG. 11 illustrates an exemplary stimulation strategy. As shown in FIG.11, functional groups may be used to establish load sharing, amplituderamping, and delayed start of stimulation to optimize the delivery ofstimulation of the targeted nerve (the Hypoglossal nerve, for example).In the exemplary strategy of FIG. 13, stimulation is delayed after apatient begins a sleep session, allowing the patient to fall asleepbefore stimulation begins. Stimulation from each of the functionalgroups takes turns ramping up, holding the tongue in the desiredposition for a period of time that is sustainable without significantfatigue, before the next group starts and the previous group stopsallowing muscle fibers associated with the previous group to relax, andwhich helps to prevent fatigue but which maintains desirable tongueposition all the time.

The remaining effort in programming the two or more electrode contactsis to select electrode contacts and assign them to functional groups.During stimulation, only a single functional group will be on at a timeor on at overlapping out of phase intervals, but a group may containmore than one contact. The effect of having more than one contact shouldadditionally be tested to make sure that the sensation of the twocontacts or groups on at the same time does not result in discomfort forthe patient. Ostensibly, if a single contact results in good airwayopening there is little reason to add another contact to the sametargeted efferent. If the use of two contacts provides better openingthen the pair should be tested together and assigned to the same group.

In certain embodiments, at least two functional groups are defined, sothat the load of maintaining tongue position is shared, prolonging thetime until fatigue sets in or preventing it altogether. Stimulationstarts with the first group, which ramps up in amplitude to a targetamplitude, stays at the target level for a pre-determined amount of timeand then is replaced or overlapped by the next group. This repeatsthrough one or more of the functional groups. The pattern may repeatbeginning with the first functional group, but need not begin with thesame functional group each time. In certain exemplary embodiments, thegroups may be programmed to ramp up in amplitude while the previousgroup is still on and at the target level of the next group the firstgroup would be programmed to terminate. This would maintain a constant,continuous level of stimulation that is shared amongst the programmedgroups. The cycle repeats until the end of the sleep session.

The load of maintaining muscle tone and position is shared by all of thefunctional groups. In one embodiment, each contact is pulsed atdifferent or overlapping intervals (FIGS. 14A and 14B). This prevents orminimizes fatigue by alternately resting and stimulating targeted musclegroups and thereby preventing the tongue from falling into a positionthat can cause apnea or hypopnea. The predetermined amount of time thata group is programmed to stay on may be determined by observing thetongue at a chosen stimulation frequency and determining how long theresulting contraction can be maintained before fatigue causes theresulting position control to degrade.

In another embodiment, each contact is pulsed at a fraction of the totaltarget frequency (discussed below) and out of phase with each of theother contacts (FIG. 4B). For example, if the target frequency is 30pps, each contact is pulsed at 10 pps with the other contactsinterleaved between each pulse rather than pulsing each contact for aninterval at 30 pps as shown in FIG. 13. In such an embodiment, thepulses are out of phase with one another so each contact pulsessequentially in a nearly continuous pattern to share the stimulationload of the contacts. Spreading the load over each of the contactsallows a much lower frequency to be used that allows for near constantmuscle stimulation without or substantially without fatigue ordiminished positioning.

Using multiple functional groups, in either a staggered or interleavedconfiguration, allows the tongue to be continuously or near-continuouslystimulated, maintaining the tongue in a desired position even thougheach functional group only stimulates its neural population for aportion of a stimulation cycle. This exemplary method maintainscontinuous or near-continuous stimulation by load sharing betweenmultiple functional groups, with each group—activating one or moredesired tongue muscle. This method has the additional feature that groupramps would occur once for a sleep session and that stimulation levelswould be maintained at their target levels, reducing the complexity ofstimulation control.

Stimulus Ramping

FIG. 13 illustrates an exemplary stimulus ramp. In certain exemplaryembodiments, a stimulus ramp is used to maximize patient comfort and/orfor prevention of arousal. With a patient who is awake, stimulationproducing a noticeable, smooth contraction is important. In treating asleeping patient suffering from obstructive sleep apnea, however,achieving the smallest contraction necessary to treat thecondition—without waking the patient—is important. The contraction onlyneeds to be sufficient to move the tongue forward enough or make airway(the pharyngeal wall) tense/rigid enough to prevent an apnea event fromoccurring, and may not even be visible to the naked eye.

The sensation of the applied electrical pulses to the nerve, and theaccompanying involuntary movement of the tongue generates is, at best,unnatural. In certain exemplary embodiments, the goal is to minimizesensation to a level acceptable to the patient. In certain exemplaryembodiments, stimulus is gradually ramped up to ease the patient up to atarget stimulus level. Stimulus starts at a threshold level, withstimulus magnitude slowly increasing to the target level. As is known tothose skilled in the art, either stimulus magnitude or phase durationmay be modulated to achieve control between the threshold and targetlevels.

If stimulation were immediately applied without a ramp, the stimulationcould awaken or arouse the patient and adversely affect their sleep,just as an apnea event would. The exemplary embodiments of the presentinvention therefore employ the method of amplitude magnitude ramps atthe start of stimulation to address this issue. The duration of thisramp is often several seconds long so that the change is gradual and thepatient is able to adjust to the delivery of stimulation to the tissue.

In certain exemplary embodiments, an amplitude ramp of approximately 5to 10 seconds is selected, (i.e., where stimulus increases to a desiredlevel in 5 to 10 seconds). Stimulation is started at the thresholdamplitude and slowly increased to the target amplitude until significanttongue movement is observed. Significant movement is defined as at leastone movement that decreases airway resistance or results in increasedairway air flow. The movement of the tongue and its affect on the airwaycan be observed with an endoscope placed in the nasal cavity, by use offluoroscopy, or by observing the front of the oral cavity and theoverall position of the tongue. Other ways of observing known to thoseskilled in the art can be used without departing from the scope of theinvention. This is the operational point or targeted stimulation levelthat will be used if it is decided that this contact is to be includedin the programmed stimulation protocol designed to affect the tongueduring the sleeping session.

Frequency Adjustment

Another factor affecting the perceived comfort for the patient is thefrequency of a pulsatile waveform. Stimulating at a very low frequency,such as approximately 1 to 3 pps, allows the easy identification of anamplitude threshold as distinct twitches or brief contractions of themuscle. These twitches or contractions are readily discernible, andoften can be felt by the patient. Increasing the frequency to asufficiently fast rate results in the fusion of the twitches (referredto as tetanus) and the relaxation between them into a smooth musclecontraction. This also quite often results in a sensation that is morecomfortable for the patient, and is it is generally more comfortable forthe patient as the frequency increases. Above a certain frequency,however, the sensation may again become uncomfortable, possiblyassociated with the level of work associated with the increased numberof muscle contractions. This comfort level must be experimentallydetermined and it can vary from patient to patient. The amplitude isthen increased to the target amplitude to sufficiently position thetongue as described above.

Delayed Stimulation Onset

In certain embodiments, stimulation is delayed until after a patient isasleep. By monitoring a patient in a sleep laboratory and/or byinterviewing a patient's partner, it can be determined how much time isnecessary to delay stimulation onset. In certain embodiments, this delayis programmed into a pulse generator. When the patient initiates a sleepsession of the device, the pulse generator then waits for the programmeddelay period to complete before applying stimulation to the Hypoglossalnerve. The delay for stimulation onset may also be associated with thepoint at which sleep apnea begins to appear in the sleep cycle of thepatient. If apneas do not begin to appear until the deepest stage ofsleep (rapid eye movement or REM) then it may be advantageous to delaythe onset of stimulation well past the point at which the patient beginsto sleep and until just before the point at which apnea becomesapparent. The stimulation may then be applied for a predetermined periodof time and/or until the pulse generator is deactivated. In oneembodiment, the pulse generator is activated and deactivated via awireless remote.

Delaying stimulation onset, using frequency and/or amplitude modulationfor a gradual ramp up or down to a desired stimulation all reduce thechances of arousing the patient in the middle of sleep, making tonicstimulation more likely to succeed. In certain treatment methods,sleeping medication for those patients who may be sensitive to theelectrical stimulation activated movement may increase the chances ofsuccessful treatment.

In an exemplary embodiment, a stimulation amplitude threshold isdetermined by initially setting a low stimulation frequency between 1and 3 pps. A typical waveform such as 200 us cathodic phase duration, 50us interphase interval and 800 us anodic phase duration is selected (theandodic phase amplitude would then be one fourth the amplitude of thecathodic phase amplitude), and then waveform amplitude is slowlyincreased from approximately 0 μA up to a level at which the tonguemuscle can be seen to twitch with each pulse, or when the patient beginsto feel the pulsatile sensation. This is the point at which theelectrical stimulation is just enough to excite fibers within the nervebundle. This setting is noted as the threshold amplitude and stimulationis stopped.

Each contact may be further tested to see what frequency should be usedfor initial stimulation. Experience and literature evidence suggeststhat the higher the frequency, the more comfortable the sensation ofelectrical stimulation is for the patient. The more comfortable thestimulation, the less likely the patient will be awakened. In theseexemplary embodiments, mulation starts at a frequency above the targetfrequency, and gradually decreases to the preferred target frequency. Apreferred frequency is a frequency comfortable to the patient thatproduces a desired stimulus response. In one embodiment, one or morecontacts deliver the target frequency at different intervals (FIGS. 13,14A). In another embodiment, the target frequency is generally dividedby the number of contacts and is spread or interleaved over the contacts(FIG. 4C).

Determining the starting frequency is performed by setting the contactstimulation parameters to those determined for target stimulation andincluding an amplitude ramp, typically 5 to 10 seconds. Stimulation isstarted and the frequency is slowly adjusted upwards, checking with thepatient for comfort. It may be necessary to reduce amplitude with higherfrequency in order to maintain comfort but if so, then the targetfrequency should be checked again at the lower amplitude to verify thatit still produces a functional movement.

Once all of the contacts have been evaluated a common higher frequencyshould be selected which is the lowest of all of the contactfrequencies. The frequency is set to the lowest contact frequency thatachieves a response resulting in increased airway airflow or decreasedairway resistance. Using the lowest frequency increases the time untilfatigue occurs. This frequency is used as the startup frequency to beused after the delay from the beginning of the session has completed.

Exemplary Method of Use

The section below describes an exemplary method of patient use of thesystem. In the method described, the patient uses a remote control andcharger (RCC) to operate and maintain the system. In this embodiment,the combination remote control and charger has a mini-USB connector,which charges an internal battery in the RCC. Optionally the RCC mayrest in a cradle kept on the patient's nightstand. The cradle would havespring loaded contacts, which make connection to the RCC much like acordless phone to charge the RCC battery. The cradle may also use amini-USB connector to attach to a wall mounted power supply.

To start a sleep session the patient uses the RCC to activate theimplantable pulse generator (IPG). In certain embodiments, the patientfirst activates the RCC, which then attempts to communicate to the IPG.If the RCC is unable to communicate with the IPG, the RCC indicates tothe patient (by, for example, beeping three times and illuminating anLED) that it could not communicate with the IPG. This might mean thatthe IPG is so low in battery power that it needs to be charged, or thatthe RCC is not close enough to communicate to the IPG. If the IPG needscharging then the patient would attach a charge coil and cable to theRCC, place the coil over the IPG, press the charge switch on the RCC andcharge the IPG until it has enough energy to stimulate, up to two orthree hours for a completely depleted IPG.

If the IPG has enough energy to communicate and is in range of the RCC,then the RCC would acquire the stimulation status and battery level.Assuming that this is the start of a normal sleep session the IPG wouldhave been in the “Stimulation Off” state. The RCC then reports thebattery status by indicating the battery LED in the green state forfull, amber for medium and red for low. If the battery level is full ormedium then the IPG would be instructed to start asleep session and theIPG On/Off LED would be set to green. If the battery were low then theIPG would be instructed to stay off and the IPG On/Off LED would be setto red. The patient could then charge the IPG to use for one or moresleep sessions.

Once a sleep session starts, the IPG initiates a startup delay periodallowing the patient to fall asleep before stimulation starts. At theend of this delay, stimulation starts with the first functional group,ramping amplitude from threshold to target amplitude and then holdingfor the remainder of its On-Time duration. In interleaved or staggeredmode, all groups would start simultaneously, utilizing their individualramp up parameters, then maintain stimulation levels at the targetlevels for the duration of the sleep period. At the beginning ofstimulation, the stimulation frequency is set to the startup frequencydetermined during programming. This frequency would be ramped downwardsto the target frequency for a programmed duration after which the targetfrequency is used.

It will be appreciated by those skilled in the art that changes could bemade to the exemplary embodiment shown and described above withoutdeparting from the broad inventive concept thereof. It is understood,therefore, that this invention is not limited to the exemplaryembodiment shown and described, but it is intended to covermodifications within the spirit and scope of the present invention asdefined by the claims. For example, “an embodiment,” and the like, maybe inserted at the beginning of every sentence herein where logicallypossible and appropriate such that specific features of the exemplaryembodiment may or may not be part of the claimed invention andcombinations of disclosed embodiments may be combined. Unlessspecifically set forth herein, the terms “a”, “an” and “the” are notlimited to one element but instead should be read as meaning “at leastone”.

Further, to the extent that the method does not rely on the particularorder of steps set forth herein, the particular order of the stepsshould not be construed as limitation on the claims. The claims directedto the method of the present invention should not be limited to theperformance of their steps in the order written, and one skilled in theart can readily appreciate that the steps may be varied and still remainwithin the spirit and scope of the present invention.

1. A method for controlling a position of a patient's tongue comprising:attaching at least one electrode to the patient's Hypoglossal nerve; andapplying an electric signal through the electrode to at least onetargeted motor efferent located within the Hypoglossal nerve tostimulate at least one muscle of the tongue.
 2. The method of claim 1,wherein the at least one electrode is programmable.
 3. The method ofclaim 2, further comprising: programming a threshold amplitude and pulseduration of the electric signal by attaching the at least oneprogrammable electrode to the patient's Hypoglossal nerve while thepatient is awake and applying the electric signal to the Hypoglossalnerve at a first frequency through the at least one programmableelectrode; and increasing at least one of the amplitude and pulseduration of the electric signal until one of the tongue moves and atleast one of the patient reports a sensation and a motion is observed.4. The method of claim 3, further comprising: programming a targetamplitude and pulse duration of the electric signal by applying thethreshold amplitude and pulse duration to the patient's Hypoglossalnerve at a second frequency through the at least one programmableelectrode, the second frequency being faster than the first frequency;and increasing at least one of the amplitude and pulse duration of theelectric signal to a target level until the tongue moves sufficiently toopen the patient's airway.
 5. The method of claim 4, further comprising:decreasing the second frequency to a target frequency.
 6. The method ofclaim 1, wherein the at least one electrode includes at least first andsecond contacts and the electric signal comprises at least first andsecond electric signals, the method further comprising: applying thefirst electric signal through the first contact to a first targetedmotor efferent located within the Hypoglossal nerve to stimulate atleast one muscle of the tongue; and applying the second electric signalthrough the second contact to a second targeted motor efferent locatedwithin the Hypoglossal nerve to stimulate at least one muscle of thetongue.
 7. The method of claim 6, wherein the at least first and secondcontacts include a plurality of contacts forming a plurality offunctional groups.
 8. The method of claim 7, wherein each functionalgroup stimulates a different muscle.
 9. The method of claim 7, whereineach functional group includes at least one of the plurality ofcontacts.
 10. The method of claim 6, wherein the first and secondelectric signals are applied at predetermined intervals.
 11. The methodof claim 6, wherein the predetermined intervals of the at least onefirst and second electric signals are out of phase with each other. 12.The method of claim 6, wherein the first and second electric signals aregenerally equal in level and frequency.
 13. The method of claim 6,wherein applying the first electric signal to the first targeted motorefferent stimulates a first muscle and applying the second electricsignal to the second targeted motor efferent stimulates a second muscle.14. The method of claim 6, wherein the first and second electric signalsare applied at predetermined cycles for alternatively resting andstimulating first and second muscles.
 15. The method of claim 6, whereinthe cessation of the first electric signal is coincident with theinitiation of the second electric signal.
 16. The method of claim 1,wherein the at least one targeted motor efferent is a protrusor motorefferent.
 17. The method of claim 1, wherein the at least one targetedmotor efferent is a muscle that moves to improve airway patency.
 18. Themethod of claim 1, wherein the electric signal is applied for apredetermined duration.
 19. The method of claim 1, wherein the electricsignal is automatically applied after the patient activates theelectrode and following a time delay sufficient to allow the patient tofall asleep.
 20. The method of claim 1, wherein the muscle is stimulatedsuch that one of apnea and hypopnea is prevented.
 21. The method ofclaim 1, wherein the electric signal is applied via an open loop system.22. The method of claim 1, wherein the electric signal is appliedcontinuously for an entire sleep period.